Both voltage-gated L-type calcium channels (responsible for the trigger Ca++) and a protein associated with SERCA, called phospholamban, are phosphorylated by cAMPdependent protein kinase. The combined action of these phosphorylations increases the amount of Ca++ in the SR. Specifically, phosphorylation of the sarcolemmal calcium channel causes more trigger Ca++ to enter the cell, and phosphorylation of phospholamban increases the activity of SERCA, thereby allowing the SR to accumulate more Ca++ before it is extruded by the 3Na+-Ca++ antiporter and the sarcolemmal Ca++ pump. The net result is that the SR releases more Ca++ into the cytosol during the next action potential, which promotes more actin-myosin interactions and hence greater force of contraction (see
Fig. 13.3 ). The increased activity of SERCA after sympathetic stimulation also results in a shortened contraction because of the rapid reaccumulation of Ca++ by the SR. This in turn allows the heart to increase its rate of relaxation. An additional consequence of sympathetic stimulation is an increase in heart rate through a direct effect on the pacemaker cells (see •Fig. 13.3 Stimulationofβ-adrenergicreceptorsintheheartincreasestheforceofcontraction.Electricalstimulationofmyocardiumresultsinatransientriseinintracellular[Ca++]andproductionofforce(A). Isoproterenol(aβ-adrenergicreceptoragonist)increasestheamplitudeoftheintracellularCa++transientandhencetheamountofforcegenerated(B). A Control B +Isoproterenol Ca Ca Force Force 0.5 sec
Additional proteins and some micropeptides also appear to be associated with SERCA and influence SR calcium transport. This includes the 34–amino acid peptide dwarf open reading frame (DWORF), which increases SERCA calcium affinity (
Fig. 13.5 ), apparently by displacing phospholamban. DWORF was identified in putative non-coding RNA.
Themechanismsunderlyingtheresponseofthehearttoβ-adrenergicstimulationarecomplexandinvolvecAMPdependentphosphorylationofseveralproteins.AnA kinase anchoring protein (AKAP) hasbeenshowntobecloselyassociatedwiththeL-typecalciumchannelintheheart,therebypositioningcAMP-dependent protein kinase closetothechannelandfacilitatingcAMP-dependentphosphorylationofthischannelduringsympatheticstimulation.HowthesecAMP-dependentphosphorylationsincreasetheamplitudeoftheintracellularCa++ transientand,insodoing,resultinamoreforceful,briefercardiaccontractionisdiscussedingeneraltermslater(seealso